Human Respiratory Syncytial Virus (hRSV) causes acute upper and lower respiratory tract infections and is a major cause for hospitalization of infants in the first year of life. Re-infection with RSV occurs frequently and sterilizing immunity is never firmly established. RSV also causes a significant disease burden and mortality in the elderly, comparable to influenza.
hRSV is an enveloped negative strand RNA virus belonging to the subfamily Pneumovirinae of the family Paramyxoviridae. Other members of this subfamily are bovine RSV (bRSV) and human metapneumovirus (hMPV). The hRSV particle contains two major glycoproteins, which are the key targets of neutralizing antibodies: the attachment protein G and the fusion protein F (review by Collins P L and J A Melero. 2011. Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Res 162:80-99). There are two RSV serotypes (A and B), which differ more in their G than F proteins. The F protein appears to be a more efficient neutralizing and protective antigen compared to G. This may be related to the high carbohydrate content of the G protein, which may shield the protein from immune recognition. In addition, the G protein is also secreted from infected cells, in which form it may function as an antigen decoy. The F protein not only functions to fuse viral and host membranes, but also plays a major role in virus-cell attachment. Neutralizing antibodies targeting F may therefore interfere with virus-cell attachment and/or with virus-cell fusion.
The RSV F protein is a type I membrane protein that is synthesized as an inactive precursor protein (named ‘F0’) that assembles into trimers. This precursor protein is cleaved by furin-like proteases into the forms named ‘F2’, ‘p27’ and ‘F1’ during its transport through the secretory route. Homotrimers of F2 and F1, which are covalently linked via disulfide bridges, form the metastable pre-fusion active structure. The F1 contains heptad repeats A and B (referred to as HRA and HRB), the fusion peptide (FP) and the transmembrane (TM) domain, the latter two positioned at opposite sides of the molecule. Upon virus-cell attachment, conformational changes in the RSV F protein lead to the insertion of the hydrophobic fusion peptide into a host cell membrane. Subsequently, this fusion intermediate refolds into a highly stable post-fusion structure. The assembly of this latter structure is dictated by the assembly of a six-helix bundle (6HB). This 6HB contains HRA and HRB of each monomer in an antiparallel conformation, as a result of which the transmembrane domain, located downstream of HRB, and the fusion peptide, located upstream of HRA, are positioned in adjacent positions and fusion of the viral and host membranes is achieved. Recent studies have elucidated the structure of the F protein in its post-fusion conformation (McLellan J S et al. 2011. J Virol 85:7788-96; Swanson K A et al. 2011. Proc Natl Acad Sci USA 108:9619-24).
hRSV vaccine development has been haunted by the disastrous results obtained with the formalin-inactivated virus vaccine that was tested in the 1960s. Disease severity and hospital admission rates were increased in vaccinated children, who were naturally infected with RSV later, and several deaths occurred. The mechanism of this vaccine-induced disease enhancement remains incompletely understood, but appears associated with low induction of neutralizing antibodies and recruitment of eosinophils. Next to this effort, a large number of RSV vaccine strategies has been explored with varying success, including live attenuated RSV strains, subunit vaccines and viral vectored vaccines (Groothuis J R et al. 2011. Prevention of serious respiratory syncytial virus-related illness. I: Disease pathogenesis and early attempts at prevention. Adv Ther 28:91-109; Hurwitz J L. 2011. Respiratory syncytial virus vaccine development. Expert Rev Vaccines 10:1415-33). Obviously, successful RSV vaccines should induce protective immunity, but no immunopathology.